Montelukast acid of formula 1 or a pharmaceutically acceptable salt thereof has been known to block or inhibit the synthesis and activity of leukotrienes, and the sodium salt thereof is currently marketed by Merck as Singulair (the registered trademark).

Leukotrienes are a group of local hormones derived from arachidonic acid in the body, and representative examples of leukotrienes include leukotriene B4 (LTB4), leukotriene C4 (LTC4), leukotriene D4 (LTD4) and leukotriene E4 (LTE4). The synthesis of such leukotrienes have been reported to involve the arachidonic acid metabolism by 5-lipoxygenase leading to the production of one of the known epoxides, i.e., leukotriene A4 (LTA4), which is immediately converted into other leukotrienes through successive enzymatic steps. The metabolism and biosynthesis of leukotrienes as well as their roles in certain diseases are reported in detail in [Leukotrienes and Lipoxygenases, ed. J. Rokach, Elsevier, Amsterdam (1989)].
European Patent No. 480,717 discloses a method for preparing the compound of formula 1 using a corresponding methyl ester compound, as shown in Reaction Scheme 1, which comprises the steps of: coupling methyl 1-(mercaptomethyl)cyclopropanylacetate of formula (II) with the methanesulfonyl intermediate of formula (I) in which the hydroxy group is protected by tetrahydropyranyl (THP) to obtain the methyl ester compound of formula (III); and hydrolyzing the methyl ester compound to obtain the corresponding free acid, which is directly converted into the corresponding sodium salt of formula (IV). However, the above method requires several complicated procedures such as protection; deprotection steps and column chromatographic separation of the product, which leads a low overall yield of the final product.

Further, in order to solve the above problem, European Patent No. 737,186 teaches a method of using the methanesulfonyl compound of formula (V) having the hydroxy group unprotected and the dilithium salt of 1-(mercaptomethyl)cyclopropanyl acetic acid of formula (VI), as shown in Reaction Scheme 2, so as to avoid the cumbersome protection; deprotection steps used in Reaction Scheme 1. This method further comprises the steps of adding dicyclohexylamine to the Montelukast acid obtained in the coupling reaction to obtain the dicyclohexylamine salt of Montelukast acid of formula (VII) in a good yield; and treating that salt with NaOH to obtain Montelukast sodium salt of formula (IV).

However, it is very difficult to prepare the compound of formula (VI) used in the coupling reaction of the above method due to the use of spontaneously combustible n-butyllithium. Further, the reaction must be conducted immediately at a very low temperature of −30° C. because of the sensitivity of the compound of formula (VI) to moisture and air.
Meanwhile, International Patent Publication No. WO 2005/105751 discloses a method for preparing Montelukast sodium salt of formula (IV), as shown in Reaction Scheme 3, which comprises the steps of: coupling the methanesulfonyl compound of formula (V) and methyl 1-(mercaptomethyl)-cyclopropylacetate of formula (II) in the presence of a base, e.g., LiOH, NaOH, NaH, NaOCH3, BuLi, LiOCH3, LiNPr2, and potassium t-butoxide (KOt-Bu) to obtain the methyl ester of formula (VIII); hydrolyzing and acidifying the compound of formula (VIII) to obtain Montelukast acid; and treating the resulting compound with NaOH, NaOCH3, or sodium t-butoxide (NaOt-Bu) to obtain Montelukast sodium salt of formula (IV).

However, the above patent teaches that the purity and yield of Montelukast acid produced by the above method are 94% and 64%, respectively, and the purity and yield of sodium montelukast, 97% and 50%, respectively, which suggests that the purity of Montelukast sodium salt obtained by this method cannot reach the required material purity of 99.3%. Accordingly, this method requires a supplementary purification procedure which is very complicated, leading to an overall yield of only 20% or less.
During the preparation of Montelukast, various structurally related impurities may form, the contents of which are required to meet specified levels, as shown in Table 1.
TABLE 1ImpurityStructureRequiredALess than 0.1% BLess than 0.2% CLess than 0.35% DLess than 0.1% ELess than 0.1% FLess than 0.2%
Moreover, the level of the combined total impurities must not exceed 0.7% of the Montelukast sodium salt product, and accordingly, the purity of Montelukast acid, the precursory compound of Montelukast sodium salt, must be high, in the range of 98% to 99%. However, it is difficult to meet such requirement when the conventional methods are used.